High Free Energy Barrier Research Articles

Coarse-Grained Molecular Dynamics with Normalizing Flows.

We propose a sampling algorithm relying on a collective variable (CV) of midsize dimension modeled by a normalizing flow and using nonequilibrium dynamics to propose full configurational moves from the proposition of a refreshed value of the CV made by the flow. The algorithm takes the form of a Markov chain with nonlocal updates, allowing jumps through energy barriers across metastable states. The flow is trained throughout the algorithm to reproduce the free energy landscape of the CV. The output of the algorithm is a sample of thermalized configurations and the trained network that can be used to efficiently produce more configurations. We show the functioning of the algorithm first in a test case with a mixture of Gaussians. Then, we successfully tested it on a higher-dimensional system consisting of a polymer in solution with a compact state and an extended stable state separated by a high free energy barrier.

Probing Nonadiabaticity of Proton-Coupled Electron Transfer in Ribonucleotide Reductase.

The enzyme ribonucleotide reductase, which is essential for DNA synthesis, initiates the conversion of ribonucleotides to deoxyribonucleotides via radical transfer over a 32 Å pathway composed of proton-coupled electron transfer (PCET) reactions. Previously, the first three PCET reactions in the α subunit were investigated with hybrid quantum mechanical/molecular mechanical (QM/MM) free energy simulations. Herein, the fourth PCET reaction in this subunit between C439 and guanosine diphosphate (GDP) is simulated and found to be slightly exoergic with a relatively high free energy barrier. To further elucidate the mechanisms of all four PCET reactions, we analyzed the vibronic and electron-proton nonadiabaticities. This analysis suggests that interfacial PCET between Y356 and Y731 is vibronically and electronically nonadiabatic, whereas PCET between Y731 and Y730 and between C439 and GDP is fully adiabatic and PCET between Y730 and C439 is in the intermediate regime. These insights provide guidance for selecting suitable rate constant expressions for these PCET reactions.

Is aromaticity loss necessary for transition-metal promoted arene-alkene cycloadditions?

Computed gas-phase reaction profiles for Diels-Alder reactions, nucleus-independent chemical shifts, and bonding analyses for substituted and metal complexed, η2-, η4-, η6-coordinated arenes reveal that dearomatization is necessary for arenes to exhibit ene- and diene-like reactivity. Substituted arenes and η6-arenes exhibit high free energy barriers towards cycloaddition reactions, but strongly dearomatized η2- and η4-arenes can display low free energy barriers (∼20 kcal mol-1 or less) for [4 + 2] cycloaddition reactions.

Permutationally Invariant Networks for Enhanced Sampling (PINES): Discovery of Multimolecular and Solvent-Inclusive Collective Variables.

The typically rugged nature of molecular free-energy landscapes can frustrate efficient sampling of the thermodynamically relevant phase space due to the presence of high free-energy barriers. Enhanced sampling techniques can improve phase space exploration by accelerating sampling along particular collective variables (CVs). A number of techniques exist for the data-driven discovery of CVs parametrizing the important large-scale motions of the system. A challenge to CV discovery is learning CVs invariant to the symmetries of the molecular system, frequently rigid translation, rigid rotation, and permutational relabeling of identical particles. Of these, permutational invariance has proved a persistent challenge in frustrating the data-driven discovery of multimolecular CVs in systems of self-assembling particles and solvent-inclusive CVs for solvated systems. In this work, we integrate permutation invariant vector (PIV) featurizations with autoencoding neural networks to learn nonlinear CVs invariant to translation, rotation, and permutation and perform interleaved rounds of CV discovery and enhanced sampling to iteratively expand the sampling of configurational phase space and obtain converged CVs and free-energy landscapes. We demonstrate the permutationally invariant network for enhanced sampling (PINES) approach in applications to the self-assembly of a 13-atom argon cluster, association/dissociation of a NaCl ion pair in water, and hydrophobic collapse of a C45H92 n-pentatetracontane polymer chain. We make the approach freely available as a new module within the PLUMED2 enhanced sampling libraries.

Spectral statistics of a minimal quantum glass model

Glasses have the interesting feature of being neither integrable nor fully chaotic. They thermalize quickly within a subspace but thermalize much more slowly across the full space due to high free energy barriers which partition the configuration space into sectors. Past works have examined the Rosenzweig-Porter (RP) model as a minimal quantum model which transitions from localized to chaotic behavior. In this work we generalize the RP model in such a way that it becomes a minimal model which transitions from glassy to chaotic behavior, which we term the “Block Rosenzweig-Porter” (BRP) model. We calculate the spectral form factors of both models at all timescales larger than the inverse spectral width. Whereas the RP model exhibits a crossover from localized to ergodic behavior at the Thouless timescale, the new BRP model instead crosses over from glassy to fully chaotic behavior, as seen by a change in the steepness of the ramp of the spectral form factor.

Moderate binding of villin headpiece protein to C3N3 nanosheet reveals the suitable biocompatibility of this nanomaterial

Since its recent successful synthesis and due to its promising physical and chemical properties, the carbon nitrite nanomaterial, C3N3, has attracted considerable attention in various scientific areas. However, thus far, little effort has been devoted to investigating the structural influence of the direct interaction of this 2D nanomaterial and biomolecules, including proteins and biomembranes so as to understand the physical origin of its bio-effect, particularly from the molecular landscape. Such information is fundamental to correlate to the potential nanotoxicology of the C3N3 nanomaterial. In this work, we explored the potential structural influence of a C3N3 nanosheet on the prototypical globular protein, villin headpiece (HP35) using all-atom molecular dynamics (MD) simulations. We found that HP35 could maintain its native conformations upon adsorption onto the C3N3 nanosheet regardless of the diversity in the binding sites, implying the potential advantage of C3N3 in protecting the biomolecular structure. The adsorption was mediated primarily by vdW interactions. Moreover, once adsorbed on the C3N3 surface, HP35 remains relatively fixed on the nanostructure without a distinct lateral translation, which may aid in keeping the structural integrity of the protein. In addition, the porous topological structure of C3N3 and the special water layer present on the C3N3 holes conjointly contributed to the restricted motion of HP35 via the formation of a high free energy barrier and a steric hindrance to prevent the surface displacement. This work revealed for the first time the potential influence of the 2D C3N3 nanomaterial in the protein structure and provided the corresponding in-depth molecular-level mechanism, which is valuable for future applications of C3N3 in bionanomedicine.

Molecular Dynamics Simulation Study of the Protonation State Dependence of Glutamic Acid Transport through a Cyclic Peptide Nanotube.

The effect of the protonation state of glutamic acid on its translocation through cyclic peptide nanotubes (CPNs) was assessed by using molecular dynamics (MD) simulations. Anionic (GLU-), neutral zwitterionic (GLU0), and cationic (GLU+) forms of glutamic acid were selected as three different protonation states for an analysis of energetics and diffusivity for acid transport across a cyclic decapeptide nanotube. Based on the solubility-diffusion model, permeability coefficients for the three protonation states of the acid were calculated and compared with experimental results for CPN-mediated glutamate transport through CPNs. Potential of mean force (PMF) calculations reveal that, due to the cation-selective nature of the lumen of CPNs, GLU-, so-called glutamate, shows significantly high free energy barriers, while GLU+ displays deep energy wells and GLU0 has mild free energy barriers and wells inside the CPN. The considerable energy barriers for GLU- inside CPNs are mainly attributed to unfavorable interactions with DMPC bilayers and CPNs and are reduced by favorable interactions with channel water molecules through attractive electrostatic interactions and hydrogen bonding. Unlike the distinct PMF curves, position-dependent diffusion coefficient profiles exhibit comparable frictional behaviors regardless of the charge status of three protonation states due to similar confined environments imposed by the lumen of the CPN. The calculated permeability coefficients for the three protonation states clearly demonstrate that glutamic acid has a strong protonation state dependence for its transport through CPNs, as determined by the energetics rather than the diffusivity of the protonation state. In addition, the permeability coefficients also imply that GLU- is unlikely to pass through a CPN due to the high energy barriers inside the CPN, which is in disagreement with experimental measurements, where a considerable amount of glutamate permeating through the CPN was detected. To resolve the discrepancy between this work and the experimental observations, several possibilities are proposed, including a large concentration gradient of glutamate between the inside and outside of lipid vesicles and bilayers in the experiments, the glutamate activity difference between our MD simulations and experiments, an overestimation of energy barriers due to the artifacts imposed in MD simulations, and/or finally a transformation of the protonation state from GLU- to GLU0 to reduce the energy barriers. Overall, our study demonstrates that the protonation state of glutamic acid has a strong effect on the transport of the acid and suggests a possible protonation state change for glutamate permeating through CPNs.

Insight into the role of excess hydroxide ions in silicate condensation reactions.

The formation of silicate oligomers in the early stages is key to zeolite synthesis. The pH and the presence of hydroxide ions are important in regulating the reaction rate and the dominant species in solutions. This paper describes the formation of silicate species, from dimers to 4-membered rings, using ab initio molecular dynamics simulations in explicit water molecules with an excess hydroxide ion. The thermodynamic integration method was used to calculate the free energy profile of the condensation reactions. The hydroxide group's role is not only to control the pH of the environment, but also to actively participate in the condensation reaction. The results show that the most favorable reactions are linear-tetramer and 4-membered-ring formation, with overall barriers of 71 kJ mol-1 and 73 kJ mol-1, respectively. The formation of trimeric silicate, with the largest free-energy barrier of 102 kJ mol-1, is the rate-limiting step under these conditions. The excess hydroxide ion aids in the stabilization of the 4-membered-ring structure over the 3-membered-ring structure. Due to a relatively high free-energy barrier, the 4-membered ring is the most difficult of the small silicate structures to dissolve in the backward reaction. This study is consistent with the experimental observation that silicate growth in zeolite synthesis is slower in a very-high-pH environment.

Unveiling the Mechanisms of Hydrolytic Ring-Opening Polymerization of Caprolactam and Amino-Assisted Ring Opening of Cyclic Dimers: A DFT Study

At the M06-2X/6-31+G(d,p) computational level, the reactions hydrolytic ring-opening polymerization of caprolactam to form cyclodimers and amino-assisted ring opening of the cyclic caprolactam dimers were studied in detail. For the above-mentioned reactions, free energy barriers were calculated and the possible reaction pathways were discussed. Our calculated results showed that the hydrolytic ring-opening polymerization reaction includes four stages. The first three stages contain two steps: nucleophilic addition and proton transfer. After finishing stage 3, a cyclic caprolactam dimer is formed by the rate-determining step─backbiting of the amino end groups. For the amino-assisted ring-opening reaction of the cyclic caprolactam dimer, the rate-determining step is stage 3 due to its highest free energy barrier. This stage can take place via a concerted or stepwise pathway. Under the experimental conditions, hydrolytic ring-opening polymerization and amino-assisted ring opening of the cyclic caprolactam dimer can be easily carried out. This study provides a theoretical basis for the effective removal of caprolactam oligomers.

Highly efficient and highly selective CO2 reduction to CO driven by laser

<h2>Summary</h2> Carbon dioxide (CO₂) reduction is a possible way to solve the greenhouse effect. Conventional catalytic CO₂ reduction faces some problems, such as high free energy barriers, limitation of cheap and effective catalysts. Here, we develop a highly efficient and highly selective CO₂ reduction under mild conditions by laser reduction in liquid (LRL). A high CO yield of 12.3 mmol h⁻¹ with near 100% selectivity and 13.3% energy conversion efficiency of laser to CO is achieved. In LRL, abundant active species are created immediately by laser-induced plasma in small bubbles along with transient extremely high temperature. Thermodynamically, CO₂ reduction proceeds quickly with the interaction of active species at high temperature. Kinetically, the rapid quenching process inhibits reverse reaction and keeps products at initial stage. The synergy of thermodynamics and kinetics results in high yield and high selectivity. These findings provide an alternative approach for CO₂ reduction under ambient conditions.

Synergistic Effects of Keggin-Type Phosphotungstic Acid-Supported Single-Atom Catalysts in a Fast NH3-SCR Reaction

Fast selective catalytic reduction of nitrogen oxide with ammonia (NH3-SCR) (2NH3 + NO2 + NO → 2N2 + 3H2O) has aroused great interest in recent years because it is inherently faster than the standard NH3-SCR reaction (4NO + 4NH3 + O2 → 4N2 + 6H2O). In the present paper, the mechanism of the fast NH3-SCR reaction catalyzed by a series of single-atom catalysts (SACs), M1/PTA SACs (PTA = Keggin-type phosphotungstic acid, M = Mn, Fe, Co, Ni, Ru, Rh, Pd, Ir, and Pt), has been systematically studied by means of density functional theory (DFT) calculations. Molecular geometry and electronic structural analysis show that Jahn-Teller distortion effects promote an electron transfer process from N-H bonding orbitals of the NH3 molecule to the symmetry-allowed d orbitals (dxy and dx2-y2) of the single metal atom, which effectively weakens the N-H bond of the adsorbed NH3 molecule. The calculated free energy profiles along the favorable catalytic path show that decomposition of NH3 to *NH2 and *H species and decomposition of *NHNOH into N2 and H2O have high free energy barriers in the whole fast NH3-SCR path. A good synergistic effect between the Brønsted acid site (surface oxygen atom in the PTA support) and the Lewis acid site (single metal atom) effectively enhances the decomposition of NH3 to *NH2 and *H species. M1/PTA SACs (M = Ru, Rh, Pd, and Pt) were found to have potential for fast NH3-SCR reaction because of the relatively small free energy barrier and strong thermodynamic driving forces. We hope our computational results could provide some new ideas for designing and fabricating fast NH3-SCR catalysts with high activity.

Synthesis mechanism of dimethylhexane-1,6-dicarbamate from 1,6-hexamethylenediamine, urea and methanol: A molecular scale study based on density functional theory

This work provides a molecular scale insight into non-phosgene synthesis based on the reaction of dimethylhexane-1,6-dicarbamate from 1,6-hexamethylenediamine, urea and methanol with computational electronic method. By exploring almost all possible reaction modes and comparing the effective barrier of each channel, this work analyzes the optimal reaction mechanism for both non-catalytic and self-catalytic systems. The mechanism without catalysis has a high effective free energy barrier (FEB) of 47.0 kcal mol−1. As for self-catalytic system, after sorting out the reaction pathway network, an effective FEB of 24.6 kcal mol−1 is confirmed which corresponds to dissociation of urea.

Improving the Efficiency of Variationally Enhanced Sampling with Wavelet-Based Bias Potentials.

Collective variable-based enhanced sampling methods are routinely used on systems with metastable states, where high free energy barriers impede the proper sampling of the free energy landscapes when using conventional molecular dynamics simulations. One such method is variationally enhanced sampling (VES), which is based on a variational principle where a bias potential in the space of some chosen slow degrees of freedom, or collective variables, is constructed by minimizing a convex functional. In practice, the bias potential is taken as a linear expansion in some basis function set. So far, primarily basis functions delocalized in the collective variable space, like plane waves, Chebyshev, or Legendre polynomials, have been used. However, there has not been an extensive study of how the convergence behavior is affected by the choice of the basis functions. In particular, it remains an open question if localized basis functions might perform better. In this work, we implement, tune, and validate Daubechies wavelets as basis functions for VES. The wavelets construct orthogonal and localized bases that exhibit an attractive multiresolution property. We evaluate the performance of wavelet and other basis functions on various systems, going from model potentials to the calcium carbonate association process in water. We observe that wavelets exhibit excellent performance and much more robust convergence behavior than all other basis functions, as well as better performance than metadynamics. In particular, using wavelet bases yields far smaller fluctuations of the bias potential within individual runs and smaller differences between independent runs. Based on our overall results, we can recommend wavelets as basis functions for VES.

Chain flexibility of medicinal lipids determines their selective partitioning into lipid droplets

In guiding lipid droplets (LDs) to serve as storage vessels that insulate high-value lipophilic compounds in cells, we demonstrate that chain flexibility of lipids determines their selective migration in intracellular LDs. Focusing on commercially important medicinal lipids with biogenetic similarity but structural dissimilarity, we computationally and experimentally validate that LD remodeling should be differentiated between overproduction of structurally flexible squalene and that of rigid zeaxanthin and β-carotene. In molecular dynamics simulations, worm-like flexible squalene is readily deformed to move through intertwined chains of triacylglycerols in the LD core, whereas rod-like rigid zeaxanthin is trapped on the LD surface due to a high free energy barrier in diffusion. By designing yeast cells with either much larger LDs or with a greater number of LDs, we observe that intracellular storage of squalene significantly increases with LD volume expansion, but that of zeaxanthin and β-carotene is enhanced through LD surface broadening; as visually evidenced, the outcomes represent internal penetration of squalene and surface localization of zeaxanthin and β-carotene. Our study shows the computational and experimental validation of selective lipid migration into a phase-separated organelle and reveals LD dynamics and functionalization.

Protective Mechanism of a Layer-by-Layer-Assembled Artificial Cell Wall on Probiotics.

Constructing an artificial cell wall (AFCW) based on the layer-by-layer assembly of polymer films to protect probiotics in harsh conditions is highly desirable. Early findings showed that encapsulating yeast cells by an AFCW improved the cell viability by 50% in antibiotic solution. However, the detailed molecular interaction mechanism remains unclear by experiments. Herein, two ciprofloxacin (CPFX) permeation models, including models 1 and 2 that were, respectively, composed of just the yeast cell membrane and the AFCW coating cell membrane, were investigated by molecular dynamics simulations. The free energy profiles delineating the permeation process of CPFX reveal that the permeation of CPFX through the cell membrane of model 2 is more difficult than through that of model 1. The analysis results show that the AFCW leads to two sharp increases in free energy barriers, amounting to 8.9 and 6.2 kcal/mol, thereby reducing the penetrating rate of CPFX into the cell membrane. Moreover, decomposition of the potentials of mean force into free energy components suggested that the electrostatic interactions of CPFX with the AFCW predominantly contributed to the high free energy barriers. The current results provide a good understanding of the protective mechanism of the self-assembled cell walls against CPFX and help to design other AFCWs.

Influence of Aqueous Arginine Solution on Regulating Conformational Stability and Hydration Properties of the Secondary Structural Segments of a Protein at Elevated Temperatures: A Molecular Dynamics Study.

The effects of aqueous arginine solution on the conformational stability of the secondary structural segments of a globular protein, ubiquitin, and the structure and dynamics of the surrounding water and arginine were examined by performing atomistic molecular dynamics (MD) simulations. Attempts have been made to identify the osmolytic efficacy of arginine solution, and its influence in guiding the hydration properties of the protein at an elevated temperature of 450 K. The similar properties of the protein in pure water at elevated temperatures were computed and compared. Replica exchange MD simulation was performed to explore the arginine solution's sensitivity in stabilizing the protein conformations for a wide range of temperatures (300-450 K). It was observed that although all the helices and strands of the protein undergo unfolding at elevated temperature in pure water, they exhibited native-like conformational dynamics in the presence of arginine at both ambient and elevated temperatures. We find that the higher free energy barrier between the folded native and unfolded states of the protein primarily arises from the structural transformation of α-helix, relative to the strands. Our study revealed that the water structure around the secondary segments depends on the nature of amino acid compositions of the helices and strands. The reorientation of water dipoles around the helices and strands was found hindered due to the presence of arginine in the solution; such hindrance reduces the possibility of exchange of hydrogen bonds that formed between the secondary segments of protein and water (PW), and as a result, PW hydrogen bonds take longer time to relax than in pure water. On the other hand, the origin of slow relaxation of protein-arginine (PA) hydrogen bonds was identified to be due to the presence of different types of protein-bound arginine molecules, where arginine interacts with the secondary structural segments of the protein through multiple/bifurcated hydrogen bonds. These protein-bound arginine formed different kinds of bridged PA hydrogen bonds between amino acid residues of the same secondary segments or among multiple bonds and helped protein to conserve its native folded form firmly.

Efficient sampling of high-dimensional free energy landscapes using adaptive reinforced dynamics.

Enhanced sampling methods such as metadynamics and umbrella sampling have become essential tools for exploring the configuration space of molecules and materials. At the same time, they have long faced a number of issues such as the inefficiency when dealing with a large number of collective variables (CVs) or systems with high free energy barriers. Here we show that, with clustering and adaptive tuning techniques, the reinforced dynamics (RiD) scheme can be used to efficiently explore the configuration space and free energy landscapes with a large number of CVs or systems with high free energy barriers. We illustrate this by studying various representative and challenging examples. First we demonstrate the efficiency of adaptive RiD compared with other methods and construct the nine-dimensional (9D) free energy landscape of a peptoid trimer, which has energy barriers of more than 8 kcal mol-1. We then study the folding of the protein chignolin using 18 CVs. In this case, both the folding and unfolding rates are observed to be 4.30 μs-1. Finally, we propose a protein structure refinement protocol based on RiD. This protocol allows us to efficiently employ more than 100 CVs for exploring the landscape of protein structures and it gives rise to an overall improvement of 14.6 units over the initial global distance test-high accuracy (GDT-HA) score.

Investigating the Conformational Dynamics of a Y-Family DNA Polymerase during Its Folding and Binding to DNA and a Nucleotide.

During DNA polymerization, the Y-family DNA polymerases are capable of bypassing various DNA damage, which can stall the replication fork progression. It has been well acknowledged that the structures of the Y-family DNA polymerases have been naturally evolved to undertake this vital task. However, the mechanisms of how these proteins utilize their unique structural and conformational dynamical features to perform the translesion DNA synthesis are less understood. Here, we developed structure-based models to study the precatalytic DNA polymerization process, including DNA and nucleotide binding to DPO4, a paradigmatic Y-family polymerase from Sulfolobus solfataricus. We studied the interplay between the folding and the conformational dynamics of DPO4 and found that DPO4 undergoes first unraveling (unfolding) and then folding for accomplishing the functional “open-to-closed” conformational transition. DNA binding dynamically modulates the conformational equilibrium in DPO4 during the stepwise binding through different types of interactions, leading to different conformational distributions of DPO4 at different DNA binding stages. We observed that nucleotide binding induces modulation of a few contacts surrounding the active site of the DPO4–DNA complex associated with a high free energy barrier. Our simulation results resonate with the experimental evidence that the conformational change at the active site led by nucleotide is the rate-limiting step of nucleotide incorporation. In combination with localized frustration analyses, we underlined the importance of DPO4 conformational dynamics and fluctuations in facilitating DNA and nucleotide binding. Our findings offer mechanistic insights into the processes of DPO4 conformational dynamics associated with the substrate binding and contribute to the understanding of the “structure–dynamics–function” relationship in the Y-family DNA polymerases.

Theoretical Study on Ethylene Polymerization Catalyzed by Half-Titanocenes Bearing Different Ancillary Groups

Half-titanocenes are well known to show high activity for ethylene polymerization and good capability for copolymerization of ethylene with other olefins, and the ancillary ligands can crucially affect the catalytic performance. In this paper, the mechanisms of ethylene polymerization catalyzed by three half-metallocenes, (η5-C5Me5)TiCl2(O-2,6-iPr2C6H3) (1), (η5-C5Me5)TiCl2(N=CtBu2) (2) and [Me2Si(η5-C5Me4)(NtBu)]TiCl2 (3), have been investigated by density functional theory (DFT) method. At the initiation stage, a higher free energy barrier was determined for complex 1, probably due to the presence of electronegative O atom in phenoxy ligand. At the propagation stage, front-side insertion of the second ethylene is kinetically more favorable than back-side insertion for complexes 1 and 2, while both side insertion orientations are comparable for complex 3. The energy decomposition showed that the bridged cyclopentadienyl amide ligand could enhance the rigidity of the active species as suggested by the lowest deformation energy derived from 3. At the chain termination stage, β-H transfer was calculated to be a dominant chain termination route over β-H elimination, presumably owing to the thermodynamic perspective.

XNgNSi (X = HCC, F; Ng = Kr, Xe, Rn): A New Class of Metastable Insertion Compounds Containing Ng-C/F and Ng-N Bonds and Possible Isomerization therein.

Recently, astronomically important silaisocyanoacetylene (HCCNSi) possessing a large dipole moment has been detected for the first time with the help of crossed molecular beam experiments. Quantum chemical computations at higher levels of theory have also been performed to characterize the transient species. In this study, we have analyzed the equilibrium geometry, stability, reactivity, and energetics as well as the nature of bonding in the noble gas (Ng) inserted HCCNSi compound. We have also considered its F analogue to understand the influence of the most electronegative atom in the compound. Metastable behavior of the XNgNSi compounds (X = HCC, F; Ng = Kr-Rn) is examined by calculating thermochemical parameters like free energy change (ΔG) and zero-point-energy-corrected dissociation energy (D0) at 298 K for all possible two-body (2B) and three-body (3B) (both neutral as well as ionic) dissociation channels using coupled-cluster theory [CCSD(T)] in addition to density functional theory (DFT) as well as second order Møller-Plesset perturbation theory (MP2). The set of predicted compounds is found to be endergonic in nature, having high positive free energy change suggesting the thermochemical stability of the compounds except for the 2B Ng-release paths. Though thermodynamically feasible, they are kinetically protected with very high activation free energy barriers. Interestingly, the release of Ng from the parent moiety XNgNSi produces the XSiN isomer, by 180° flipping of the NSi moiety. This can also be seen in the dynamical simulation carried out with the help of atom-centered density matrix propagation (ADMP) technique at 2000K for 1 ps. The bonding in Ng-C, Ng-F, and Ng-N bonds of the studied compounds is analyzed and described with the aid of natural bond orbital (NBO), topological parameters computed using atoms-in-molecules theory (AIM), energy decomposition analysis (EDA), and adaptive natural density partitioning (AdNDP) methods. The natural charge distribution on the constituent atoms suggests that the compounds can be partitioned into both ways of representations, viz., neutral radical as well as ionic fragments. Lastly, the reactivity of the compounds is scrutinized using certain reactivity descriptors calculated within the domain of conceptual density functional theory (CDFT).